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Search Results: 1 - 10 of 78 matches for " Stian Knappskog "
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Adjuvant treatment: the contribution of expression microarrays
Per L?nning, Ranjan Chrisanthar, Vidar Staalesen, Stian Knappskog, Johan Lillehaug
Breast Cancer Research , 2007, DOI: 10.1186/bcr1812
Abstract: The first study to explore human breast cancer biology applying gene expression signatures was that reported by Perou and coworkers [3] in 2000. Here, oestrogen receptor (ER)-positive breast cancers (designated luminal class, based on cytokeratin expression) were found to be associated with particular gene expression profiles. Moreover, the gene expression signatures revealed (at least) two distinct subclasses among the ER-positive tumours, termed luminal A and luminal B. This subclassification provided novel prognostic information. Thus, among patients with locally advanced breast cancers undergoing primary chemotherapy with either doxorubicin monotherapy [4] or 5-fluorouracil and mitomycin given in concert [5] to be followed by tamoxifen adjuvant for 5 years, a poor prognosis was identified among patients with tumours expressing a luminal B profile as opposed to the luminal A group [6]. Interestingly, when the classification was applied to a second cohort of patients with early stage breast cancers who had not received adjuvant endocrine therapy [7], again the luminal A and B classes were associated with different prognosis; the relative difference, however, was much less than that in patients receiving tamoxifen treatment. Although this could indicate a predictive component (higher sensitivity for luminal A class tumours to tamoxifen treatment compared with luminal B ones), such conclusions should not be inferred from indirect comparison.The second major achievement was further subclassification within the group of ER-negative tumours. This led to identification of the so-called 'triple negative' class (tumours negative with respect to expression of ER and progesterone receptor that, in addition, lack over-expression and/or amplification of HER2) as a distinct subclass. These triple negative tumours expressed keratin markers that are strongly suggestive of a basal cell origin (for which reason they are frequently referred to as 'basal cell class' tumours), contra
Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers
Bj?rnslett Merete,Knappskog Stian,L?nning Per,D?rum Anne
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-454
Abstract: Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465). Results The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer. Conclusions Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.
Inverse Regulation of EGFR/HER1 and HER2-4 in Normal and Malignant Human Breast Tissue
Marianne Hauglid Fl?geng, Stian Knappskog, Ben P. Haynes, Per Eystein L?nning, Gunnar Mellgren
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074618
Abstract: Cross-talk between the estrogen and the EGFR/HER signalling pathways has been suggested as a potential cause of resistance to endocrine therapy in breast cancer. Here, we determined HER1-4 receptor and neuregulin-1 (NRG1) ligand mRNA expression levels in breast cancers and corresponding normal breast tissue from patients previously characterized for plasma and tissue estrogen levels. In tumours from postmenopausal women harbouring normal HER2 gene copy numbers, we found HER2 and HER4, but HER3 levels in particular, to be elevated (2.48, 1.30 and 22.27 –fold respectively; P<0.01 for each) compared to normal tissue. Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively). HER2 and HER3 expression levels correlated positively with ER mRNA (ESR1) expression levels (r=0.525, P=0.044; r=0.707, P=0.003, respectively). In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001). In addition, EGFR/HER1 correlated negatively to intra-tumour (r=-0.633, P=0.001) as well as normal tissue (r=-0.556, P=0.006) and plasma estradiol levels (r=-0.625, P=0.002), suggesting an inverse regulation between estradiol and EGFR/HER1 levels. In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020). Our results indicate influence of estradiol on the expression of multiple components of the HER system in tumours not amplified for HER2, adding further support to the hypothesis that cross-talk between these systems may be of importance to breast cancer growth in vivo.
Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer
Stian Knappskog, Ranjan Chrisanthar, Erik L?kkevik, Gun Anker, Bj?rn ?stenstad, Steinar Lundgren, Terje Risberg, Ingvil Mjaaland, Beryl Leirvaag, Hrvoje Miletic, Per E L?nning
Breast Cancer Research , 2012, DOI: 10.1186/bcr3147
Abstract: We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status.While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5).Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.Despite significant improvements in cancer therapy over the last decades, resistance towards chemotherapy remains the main obstacle to cure among patients suffering from solid tumors [1].The molecular mechanisms causing chemo-resistance in breast cancer, as for most other cancer forms, are poorly understood. While Topoisomerase-II amplified tumors on average reveal enhanced anthracycline sensitivity compared to non-amplified tumors [2-5], lack of Topoisomerase-II expression may not explain anthracycline resistance.p53, the tumor suppressor protein encoded by the TP53 gene, plays a key role with respect to apoptosis but also senescence, growth arrest and DNA repair [6,7]. Our group has previously linked mutations in TP53, (in particular those affect
Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers
Elisabet Berge, Stian Knappskog, Stephanie Geisler, Vidar Staalesen, Marec Pacal, Anne-Lise B?rresen-Dale, P?l Puntervoll, Johan Lillehaug, Per L?nning
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-173
Abstract: Analyzing 73 locally advanced (stage III) breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution in the pRb protein (Leu607Ile, Arg698Trp, and Arg621Cys, respectively). This is the first study reporting point mutations affecting RB1 in breast cancer tissue. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23) with the exons 21-23 deletion occurring in the tumor also harboring the Leu607Ile mutation. Interestingly, Leu607Ile and Arg621Cys point mutations both localize to the spacer region of the pRb protein, a region previously shown to harbor somatic and germline mutations. Multiple sequence alignment across species indicates the spacer to be evolutionary conserved. All three RB1 point mutations encoded nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro. Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either 5-FU/mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046).Although rare, our findings suggest RB1 mutations to be of pathological importance potentially affecting sensitivity to mitomycin/anthracycline treatment in breast cancer.The retinoblastoma gene (RB1) is a tumor suppressor gene. pRb, the protein coded for by the RB1 gene, plays a pivotal role in cell cycle regulation, promoting G1/S arrest and growth restriction through inhibition of the E2F transcription factors [1]. Germline mutations affecting the RB1 gene are strongly associated with retinoblastoma development in children, and recent evidence has revealed an increased risk of different malignancies, including breast cancers, among patients cured from hereditary retinoblastoma [2].Somatic alterations of the RB1 gene have been detected in different malignancies [3-5]. Previous studies have reported allelic imbalance (AI), loss of pRb protei
CHEK2 Mutations Affecting Kinase Activity Together With Mutations in TP53 Indicate a Functional Pathway Associated with Resistance to Epirubicin in Primary Breast Cancer
Ranjan Chrisanthar, Stian Knappskog, Erik L?kkevik, Gun Anker, Bj?rn ?stenstad, Steinar Lundgren, Elisabet O. Berge, Terje Risberg, Ingvil Mjaaland, Lovise M?hle, Lars Fredrik Engebretsen, Johan Richard Lillehaug, Per Eystein L?nning
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003062
Abstract: Background Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14(ARF) genes; and 4) Explore potential CHEK2 or p14(ARF) germline mutations with respect to family cancer incidence. Methods and Findings Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14(ARF) mutations by sequencing the coding region and p14(ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14(ARF) were detected. Conclusion This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel
Ranjan Chrisanthar,Stian Knappskog,Erik L?kkevik,Gun Anker,Bj?rn ?stenstad,Steinar Lundgren,Terje Risberg,Ingvil Mjaaland,Gudbrand Skj?nsberg,Turid Aas,Ellen Schlichting,Hans E. Fj?sne,Arne Nysted,Johan Richard Lillehaug,Per Eystein L?nning
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019249
Abstract: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.
A paycheck half-empty or half-full? Framing, fairness and progressive taxation
Stian Reimers
Judgment and Decision Making , 2009,
Abstract: Taxation policy is driven by many factors, including public opinion, but little research has examined the strength and stability of the public's taxation preferences. This paper demonstrates one way in which preferences for progressiveness depend on the framing of the question asked. Participants indicated how they would share a fixed tax burden between two individuals who earned different amounts of money, either by adjusting the amount of tax paid by the two individuals, or by adjusting the amount of post-tax income retained. The units in which tax was described --- amount of money or percentage tax rate --- were manipulated orthogonally. There was a strong metric effect: Participants favored progressiveness more when tax was described as a percentage rather than amount. However, there was also a clear interaction: for amounts, participants favored progressiveness significantly more when considering post-tax money retained rather than tax paid; for percentages, no such effect was found.
Motivasjon for deltakelse i helseunders kelser
Stian Antonsen
Norsk Epidemiologi , 2009,
Abstract: Artikkelen tar utgangspunkt i de siste ti renes markerte kning i frafallet i helseunders kelser, med s rlig fokus p helseunders kelsen i Nord-Tr ndelag (HUNT). Foruten gi en gjennomgang av hvilke grupper som vanligvis er underrepresenterte i helseunders kelser, diskuterer artikkelen ulike tiltak som kan bidra til redusere frafallet. Datamaterialet best r av fem fokusgrupper. Funnene fra studien viser at den opplevde egennytten er den viktigste faktoren for beslutningen om delta i helseunders kelser, men at nsket om bidra til forskning ogs er sv rt viktig for motivasjonen til delta. At det bidra til forskning oppfattes som s pass viktig, bryter med den bytteteoretiske logikken som ligger til grunn for mye av den samfunnsvitenskapelige forskningen om frafallsreduksjon. Altruistiske motiver virker spille st rre rolle for deltakelse i helseunders kelser enn hva tilfellet er i andre typer unders kelser. Funnene antyder ogs at ulike grupper lar seg motivere av ulike strategier. S rlig virker det v re forskjeller basert p alder og utdanningsniv , uten at studien kan si noe konklusivt p dette omr det
MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk
Stian Knappskog, Liv B. Gansmo, P?l Romundstad, Merete Bj?rnslett, Jone Trovik, Jan Sommerfelt-Pettersen, Erik L?kkevik, for the Norwegian Breast Cancer Group trial NBCG VI , Rob A. E. M. Tollenaar, Caroline Seynaeve, Peter Devilee, Helga B. Salvesen, Anne D?rum, Kristian Hveem, Lars Vatten, Per E. L?nning
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036263
Abstract: The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been shown to affect cancer risk. One of these polymorphisms (SNP309T>G; rs2279744) facilitates Sp1 transcription factor binding to the promoter and is associated with increased cancer risk. In contrast, SNP285G>C (rs117039649), located 24 bp upstream of rs2279744, and in complete linkage disequilibrium with the SNP309G allele, reduces Sp1 recruitment and lowers cancer risk. Thus, fine tuning of MDM2 expression has proven to be of significant importance with respect to tumorigenesis. We assessed the potential functional effects of a third MDM2 promoter P2 polymorphism (SNP344T>A; rs1196333) located on the SNP309T allele. While in silico analyses indicated SNP344A to modulate TFAP2A, SPIB and AP1 transcription factor binding, we found no effect of SNP344 status on MDM2 expression levels. Assessing the frequency of SNP344A in healthy Caucasians (n = 2,954) and patients suffering from ovarian (n = 1,927), breast (n = 1,271), endometrial (n = 895) or prostatic cancer (n = 641), we detected no significant difference in the distribution of this polymorphism between any of these cancer forms and healthy controls (6.1% in healthy controls, and 4.9%, 5.0%, 5.4% and 7.2% in the cancer groups, respectively). In conclusion, our findings provide no evidence indicating that SNP344A may affect MDM2 transcription or cancer risk.
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